1. Technical Field
This invention relates to a method of producing corticotropin-releasing factor (CRF) antagonism employing certain 4-substituted thio-5-oxo-3-pyrazolines. The invention further relates to compounds and pharmaceutical compositions suitable for use in such a method.
2. Background Information
Although the existence of a "corticotropin releasing factor" was postulated more than 30 years ago [G. W. Harris, Physiol. Rev., 28, 139 (1948)], it was not until 1981 that the purification and sequencing of this hormone was accomplished [J. Spiess et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6517 (1981); W. Vale et al., Science, 213, 1394 (1981)]. This CRF isolated from ovine hypothalmi was identified as a 41 residue straight chain peptide. Shortly thereafter the sequences of human and rat CRF were determined. They were the same, but differed from ovine CRF (oCRF) in 7 of the 41 amino acid residues [J. Rivier et al., Proc. Natl. Acad. Sci., U.S.A., 80, 4851(1983); Furutani et al., Nature, 301, 537 (1983)].
Both types of CRF produce profound alterations in behavioral and autonomic nervous system function [G. F. Koob and F. E. Bloom, Fed. Proc., 44, 259 (1985); M. R. Brown and L. A. Fisher, Fed. Proc., 44, 243 (1985)]. When administered directly into the brain, CRF initiates behavioral, physiological and endocrine responses that are essentially identical to those observed when animals are exposed to a stressful environment. For example, intracerebroventricular (icv) injection of CRF elicits behavioral activation [R. E. Sutton et al., Nature, 297, 331 (1982)], produces a long-lasting activation of the electroencephalogram [C. L. Ehlers et al., Brain Res., 278, 332 (1983)], stimulates the sympathoadrenomedullary pathway [e.g., M. R. Brown et al., Endocrinology, 110, 928 (1982)], increases heart rate and blood pressure [L. A. Fisher et al., Endocrinology, 110, 2222 (1982)], increases oxygen consumption [M. R. Brown et al., Life Sciences., 30, 207 (1982)], alters gastrointestinal activity [C. L. Williams et al., Am. J. Physiol., 253, G582 (1987)], suppresses food consumption [A. S. Levine et al., Neuropharmacology, 22, 337 (1983 )] and sexual behavior [D. J. S. Sirinathsinghji et al., Nature, 305, 232 (1983)] and compromises immune function [M. Irwin et al., Am. J. Physiol., 255, R744 (1988)].
CRF antagonists would be expected to reverse the effects of CRF administration. CRF antagonists identified to date are restricted to peptides [C. L. Rivier, J. E. F. Rivier, W. W. Vale, Jr., and M. R. Brown, U.S. Pat. No. 4,605,642, Aug. 12, 1986; J. Rivier, C. Rivier, and W. Vale, Science, 224, 889 (1984)]. A relatively potent antagonist of CRF is .alpha.-helical CRF.sub.9-14. Evaluation of this antagonist in a host of in vitro and in vivo model systems has established the physiological role of CRF, not only in the control of corticotropin (ACTH) secretion and other proopiomelanocortin (POMC) gene products from the anterior pituitary gland, but more importantly, in the direct mediation of behavioral and physiological responses to stress [A. Tazi et al., Regul. Peptides, 18, 37 (1987); M. R. Brown et al., Regul. Peptides, 16, 321 (1986); C. L. Williams et al., Am. J. Physiol, 253, G582 (1987)].
Thus, the evidence that a CRF antagonist can attenuate the pharmacological responses to CRF is compelling and establishes the potential therapeutic utility of the compounds and compositions of this invention.